The human T lymphotropic virus type I (HTLV-I) is associated with a chronic-progressive myelopathy known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM~TSP). Since this disorder is clinically similar to the chronic-progressive form of multiple sclerosis (MS), understanding the pathogenesis of a neurologic disease with a known viral etiology such as HAM/TSP will help define similar mechanisms in the pathogenesis in MS, a disease of unknown etiology. Four major areas of research are being targeted that address the pathogenesis of HTLV-I in HAM/TSP: (1) host immune response in the HAM/TSP disease process; in particular, the role of CD8+, HTLV-I specific and HLA class I-restricted cytotoxic T lymphocytes (CTL); (2) detection of human retroviral sequences in the central nervous system and lymphoid organs of HAM/TSP patients both in situ and in vivo; (3) demonstration of HTLV-I- specific T-cell responses to immunodominant synthetic peptides of HTLV-I from HTLV-I seronegative individuals at risk for exposure to HTLV-I, and; (4) molecular characterization of human retroviruses isolated from patients with HAM/TSP and other chronic-progressive neurologic diseases. The major findings of these studies are: (1) demonstration CD8+ CTL directly isolated from PBL or CSF of HAM/TSP patients that are specific for immunodominant peptides of the tax region of HTLV-I and are restricted to particular HLA alleles; (2) exceptionally high precursor frequencies were demonstrated to these peptides in the range of 1 in 75 to 1 in 300 C8+ cells; (3) HTLV-I tax mRNA signals were detected in spinal cord lesions of HAM~TSP patients; (4) in situ -PCR was developed and successfully amplified HTLV-I tax DNA from PBL to HAM/TSP patients; (5) HTLV-I-T-cell responses to synthetic peptides of HTLV-I could be demonstrated from HTLV-I seronegative, PCR negative individuals known to be exposed to this virus; (6) HTLV-I molecular sequences were identified in an HTLV-I seronegative individual with a chronic-progressive neurologic disease; and (7) HTLV-II has been unequivocally identified, both molecularly and immunologically, in an individual with a chronic myelopathy indistinguishable from HAM/TSP. These results continue to define the role of human retroviruses that are associated with chronic-progressive neurologic disease and the host immune responses to these agents that may be involved in the pathogenesis of these disorders.